Relevance of Sympathetic Nervous System Activation in Obesity and Metabolic Syndrome
Open accessAbstract
Sympathetic tone is well recognised as being implicit in cardiovascular control. It is less readily acknowledged that activation of the sympathetic nervous system is integral in energy homeostasis and can exert profound metabolic effects. Accumulating data from animal and human studies suggest that central sympathetic overactivity plays a pivotal role in the aetiology and complications of several metabolic conditions that can cluster to form the Metabolic Syndrome (MetS). Given the known augmented risk for type 2 diabetes, cardiovascular disease, and premature mortality associated with the MetS understanding the complex pathways underlying the metabolic derangements involved has become a priority. Many factors have been proposed to contribute to increased sympathetic nerve activity in metabolic abnormalities including obesity, impaired baroreflex sensitivity, hyperinsulinemia, and elevated adipokine levels. Furthermore there is mounting evidence to suggest that chronic sympathetic overactivity can potentiate two of the key metabolic alterations of the MetS, central obesity and insulin resistance. This review will discuss the regulatory role of the sympathetic nervous system in metabolic control and the proposed pathophysiology linking sympathetic overactivity to metabolic abnormalities. Pharmacological and device-based approaches that target central sympathetic drive will also be discussed as possible therapeutic options to improve metabolic control in at-risk patient cohorts.
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The SNS increases in response to caloric surplus, with norepinephrine activating β-adrenergic receptors, particularly in BAT, stimulating UCP1 and generating heat through uncoupled respiration.
“The SNS increases in response to caloric surplus, with norepinephrine activating β-adrenergic receptors, particularly in BAT. This stimulates UCP1 in BAT mitochondria, generating heat through uncoupled respiration.”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [39]
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“Alicia A. Thorp has no conflict of interests to disclose.”
BackgroundIntralipid Enhances α 1 -Adrenergic Receptor–Mediated Pressor Sensitivity
Haastrup, A. T., Stepniakowski, K. T., Goodfriend, T. L., & Egan, B. M. (1998) · Hypertension · doi:10.1161/01.hyp.32.4.693 · Cited by 64 · see citing works
Role of leptin and central nervous system melanocortins in obesity hypertension
da Silva, A. A., Carmo, J. M. D., & Hall, J. E. (2013) · Current Opinion in Nephrology and Hypertension · doi:10.1097/mnh.0b013e32835d0c05 · Cited by 63 · cited 1× · see citing works
“In an elegant study by Straznicky et al., middle-aged subjects with the MetS who lost 9% of their body weight after undergoing a 12-week hypocaloric diet were shown to have significantly improved resting muscle sympathetic nerve activity, whole-body noradrenaline spillover, and whole-body insulin…”
BackgroundMachleidt, F., Simon, P., Krapalis, A. F., Hallschmid, M., Lehnert, H., & Sayk, F. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-3009 · Cited by 61 · see citing works
Chazova, I. E., & Schlaich, M. P. (2013) · International Journal of Hypertension · doi:10.1155/2013/541689 · Cited by 60 · cited 1× · see citing works
“6mmol/L in triglycerides, and decline of 5 beats/minute in heart rate [93].”
BackgroundSelf-citationConsequences of the Increased Autonomic Nervous Drive in Hypertension, Heart Failure and Diabetes
Julius, M. (1998) · Blood Pressure · doi:10.1080/080370598438410-1 · Cited by 55 · see citing works
Central sympatholytic therapy has anti-inflammatory properties in hypertensive postmenopausal women
Pöyhönen‐Alho, M., Manhem, K., Katzman, P., Kibarskis, A., Antikaínen, R., Erkkola, R. U., Tuomilehto, J. O., Ebeling, P. E., & Kaaja, R. (2008) · Journal of Hypertension · doi:10.1097/hjh.0b013e328311cf37 · Cited by 51 · see citing works
Straznicky, N. E., Lambert, G. W., McGrane, M. T., Masuo, K., Dawood, T., Nestel, P. J., Eikelis, N., Schlaich, M. P., Esler, M., Socratous, F., et al. (2009) · Diabetes · doi:10.2337/db08-1595 · Cited by 51 · see citing works
Self-citationThe Functional Importance of Sympathetic Nerves to the Liver and Endocrine Pancreas
Järhult, J., FALCK, B., Ingemansson, S., & Nobin, A. (1979) · Annals of Surgery · doi:10.1097/00000658-197901000-00018 · Cited by 49 · see citing works
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Metabolic Syndrome and Hyperglycemia: Congruence and Divergence
Alexander, C. M., Landsman, P. B., & Grundy, S. M. (2006) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2006.04.046 · Cited by 43 · cited 1× · see citing works
“…that govern the sympathetic nervous system are yet to be fully elucidated, sympathetic tone is recognised as an important mediator of cardiovascular function predominantly through its direct effects on beta-adrenergic receptors in the heart to modulate cardiac output and on alpha-adrenergic…”
BackgroundThe Effect of Moxonidine on Endothelial Dysfunction in Metabolic Syndrome
Topal, E., Çıkım, A. S., Çıkım, K., Temel, İ., & Оздемир, Р. (2006) · American Journal of Cardiovascular Drugs · doi:10.2165/00129784-200606050-00007 · Cited by 40 · see citing works
Lithell, H., Pollare, T., Berne, C., & Saltin, B. (1992) · Blood Pressure · doi:10.3109/08037059209065120 · Cited by 32 · see citing works
Sympathetic and haemodynamic responses to lipids in healthy human ageing
Florian, J. P., & Pawelczyk, J. A. (2010) · Experimental Physiology · doi:10.1113/expphysiol.2009.050997 · Cited by 23 · see citing works
Ciriello, J. (2013) · Peptides · doi:10.1016/j.peptides.2013.03.021 · Cited by 19 · cited 1× · see citing works
“…study by Straznicky et al., middle-aged subjects with the MetS who lost 9% of their body weight after undergoing a 12-week hypocaloric diet were shown to have significantly improved resting muscle sympathetic nerve activity, whole-body noradrenaline spillover, and whole-body insulin sensitivity.”
BackgroundRenal norepinephrine spillover during infusion of nonesterified fatty acids
Grekin, R. J., Ngarmukos, C., Williams, D. M., & Supiano, M. A. (2005) · American Journal of Hypertension · doi:10.1016/j.amjhyper.2004.10.013 · Cited by 14 · cited 1× · see citing works
“Latest findings from pharmaceutical and device-based clinical trials are encouraging for targeting central sympathetic activity to improve metabolic control in patients with the MetS who are at heightened risk for diabetes and cardiovascular disease.”
BackgroundVettor, R., Zarjevski, N., Cusin, I., et al. (1994) · Diabetologia · doi:10.1007/s001250050236 · Cited by 13 · see citing works
Lipolytic sensitivity and response to fasting in normotensive and hypertensive obese humans
Townsend, R. R., & Klein, S. (1997) · Metabolism · doi:10.1016/s0026-0495(97)90282-1 · Cited by 8 · cited 1× · see citing works
“Evidence in support of weight gain being directly related to decreased beta-adrenergic responsiveness comes from studies that show that both short-term [77] and chronic [78, 79] pharmacological blockade of beta-receptors leads to an increase in body weight.”
BackgroundMatsuzawa, Y. (1997) · doi:10.1002/(sici)1099-0895(199703)13:1
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Heart rate variability in type 2 diabetes mellitus: A systematic review and meta–analysis
Benichou, T., Pereira, B., Mermillod, M., Tauveron, I., Pfabigan, D., Maqdasy, S., & Dutheil, F. (2018) · PLOS ONE · doi:10.1371/journal.pone.0195166 · Cited by 419 · see citing works
Leggio, M., Lombardi, M., Caldarone, E., Severi, P., D’Emidio, S., Armeni, M., Bravi, V., Bendini, M. G., & Mazza, A. (2017) · Hypertension Research · doi:10.1038/hr.2017.75 · Cited by 313 · see citing works
Heart Failure With Preserved Ejection Fraction and Diabetes
McHugh, K., DeVore, A. D., Wu, J., Matsouaka, R. A., Fonarow, G. C., Heidenreich, P. A., Yancy, C. W., Green, J. B., Altman, N., & Hernandez, A. F. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.11.033 · Cited by 313 · see citing works
SGLT2 Inhibitor–Induced Sympathoinhibition
Herat, L. Y., Magno, A. L., Rudnicka, C., Hricova, J., Carnagarin, R., Ward, N. C., Arcambal, A., Kiuchi, M. G., Head, G. A., Schlaich, M. P., et al. (2020) · JACC: Basic to Translational Science · doi:10.1016/j.jacbts.2019.11.007 · Cited by 233 · see citing works
“There is clear evidence to indicate that obesity, metabolic syndrome, and type 2 diabetes are associated with chronic activation of sympathetic nervous tone (7,8).”
BackgroundSelf-citationRole of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2
Matthews, V. B., Elliot, R. H., Rudnicka, C., Hricova, J., Herat, L., & Schlaich, M. P. (2017) · Journal of Hypertension · doi:10.1097/hjh.0000000000001434 · Cited by 222 · see citing works
“Sympathetic activity is upregulated in obesity and type 2 diabetes and associated with perturbed glucose homeostasis, as recently reviewed in detail [5,6].”
BackgroundInfluentialSelf-citation‘Adipaging’: ageing and obesity share biological hallmarks related to a dysfunctional adipose tissue
Pérez, L. M., Pareja‐Galeano, H., Sanchis‐Gomar, F., Emanuele, E., Lucia, A., & Gálvez, B. G. (2016) · The Journal of Physiology · doi:10.1113/jp271691 · Cited by 215 · see citing works
“The SNS is also exceedingly active in obese adults and plays a key role in the development of insulin resistance (Thorp & Schlaich, 2015).”
BackgroundAdipokines, diabetes and atherosclerosis: an inflammatory association
Freitas‐Lima, L. C., Braga, V. A., de França-Silva, M. D. S., Cruz, J. C., Santos, S. H. S., Monteiro, M. M. D. O., & Balarini, C. M. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2015.00304 · Cited by 214 · see citing works
“Growth factors and cytokines released by inflammatory cells contribute to the formation of a fibrous cap of smooth muscle and extracellular matrix around the lipid core, which compromises vascular lumen (Ross, 1999; Lusis, 2000; Hansson et al., 2002; Libby et al., 2010).”
BackgroundA new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity
Sano, M. (2018) · Journal of Cardiology · doi:10.1016/j.jjcc.2017.12.004 · Cited by 188 · see citing works
Human adipose beiging in response to cold and mirabegron
Finlin, B. S., Memetimin, H., Confides, A. L., Kasza, I., Zhu, B., Vekaria, H. J., Harfmann, B. D., Jones, K. A., Johnson, Z., Westgate, P. M., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.121510 · Cited by 194 · see citing works
Yadav, R. L., Yadav, P. K., Yadav, L. K., Agrawal, K., Sah, S. K., & Islam, M. N. (2017) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s123935 · Cited by 193 · see citing works
Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones
Geisler, C. E., & Renquist, B. J. (2017) · Journal of Endocrinology · doi:10.1530/joe-16-0513 · Cited by 191 · see citing works
“2014, Thorp & Schlaich 2015).”
InfluentialAntipsychotic Drugs: From Receptor-binding Profiles to Metabolic Side Effects
Siafis, S., Tzachanis, D., Samara, M. T., & Papazisis, G. (2017) · Current Neuropharmacology · doi:10.2174/1570159x15666170630163616 · Cited by 186 · see citing works
“Despite the possible protective effects of beta receptor signaling, sustained sympathetic hyperactivity seems to disrupt beta receptor density and function [121].”
BackgroundDiagnosing sarcopenia: Functional perspectives and a new algorithm from the ISarcoPRM
Kara, M., Kaymak, B., Frontera, W. R., Ata, A. M., Ricci, V., Ekiz, T., Chang, K. C., Han, D., Michail, X., Quittan, M., et al. (2021) · Journal of Rehabilitation Medicine · doi:10.2340/16501977-2851 · Cited by 183 · see citing works
Barrea, L., Marzullo, P., Muscogiuri, G., Di Somma, C., Scacchi, M., Orio, F., Aimaretti, G., Colao, A., & Savastano, S. (2018) · Nutrition Research Reviews · doi:10.1017/s0954422418000136 · Cited by 171 · see citing works
“It is also worth noting that the activity of the sympathetic nervous system, which controls resting energy expenditure at the systemic and local levels((80)), is enhanced in PCOS as much as in obesity, insulin resistance and hypertension((81,82)).”
BackgroundMolecular pathways linking adipose innervation to insulin action in obesity and diabetes mellitus
Guilherme, A., Henriques, F. D. S., Bedard, A. H., & Czech, M. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0165-y · Cited by 173 · see citing works
Oussaada, S. M., van Galen, K. A., Cooiman, M. I., Kleinendorst, L., Hazebroek, E. J., van Haelst, M. M., ter Horst, K. W., & Serlie, M. J. (2019) · Metabolism · doi:10.1016/j.metabol.2018.12.012 · Cited by 180 · see citing works
Light exposure during sleep impairs cardiometabolic function
Mason, I. C., Grimaldi, D., Reid, K. J., Warlick, C., Malkani, R. G., Abbott, S. M., & Zee, P. C. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2113290119 · Cited by 151 · see citing works
“Specifically, in response to increased sympathetic outflow to skeletal muscle, postprandial glucose uptake from skeletal muscles is reduced, resulting in an increase of plasma glucose levels which, in turn, stimulate additional insulin production by the pancreas and promote insulin resistance (40).”
BackgroundPosttraumatic stress disorder: A metabolic disorder in disguise?
Michopoulos, V., Vester, A., & Neigh, G. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.05.038 · Cited by 152 · see citing works
“These mutual changes in biology are concomitant with increased inflammation and suggest a common mechanism by which exposure to trauma and coincident PTSD increases risk for the development of physical diseases, including obesity and T2DM (Rosenbaum et al., 2015).”
InfluentialChristoffersen, B. Ø., Sanchez‐Delgado, G., John, L. M., Ryan, D. H., Raun, K., & Ravussin, E. (2022) · Obesity · doi:10.1002/oby.23374 · Cited by 142 · see citing works
Impact of Obesity on Atrial Fibrillation Pathogenesis and Treatment Options
Sha, R., Baines, O., Hayes, A., Tompkins, K., Kalla, M., Holmes, A. P., O’Shea, C., & Pavlović, D. (2023) · Journal of the American Heart Association · doi:10.1161/jaha.123.032277 · Cited by 145 · see citing works
Valensi, P. E. (2021) · Cardiovascular Diabetology · doi:10.1186/s12933-021-01356-w · Cited by 138 · see citing works
“, changing energy states, food intake, carbohydrate consumption, hyperinsulinemia, and exposure to cold) via regulation of the resting metabolic rate and initiation of thermogenesis by action on the brown adipose tissue [43, 44].”
BackgroundCardiac Autonomic Neuropathy in Obesity, the Metabolic Syndrome and Prediabetes: A Narrative Review
Williams, S. M., Eleftheriadou, A., Alam, U., Cuthbertson, D. J., & Wilding, J. P. H. (2019) · Diabetes Therapy · doi:10.1007/s13300-019-00693-0 · Cited by 128 · see citing works
Sympathetic Neuronal Activation Triggers Myeloid Progenitor Proliferation and Differentiation
Vasamsetti, S. B., Florentin, J., Coppin, E., Stiekema, L. C. A., Zheng, K. H., Nisar, M. U., Sembrat, J., Levinthal, D. J., Rojas, M. M., Stroes, E. S. G., et al. (2018) · Immunity · doi:10.1016/j.immuni.2018.05.004 · Cited by 122 · see citing works
“, 2011) and humans (Esler et al., 2001; Seals and Bell, 2004; Thorp and Schlaich, 2015) has been reported.”
Hypertension as a Metabolic Disorder and the Novel Role of the Gut
Tanaka, M., & Itoh, H. (2019) · Current Hypertension Reports · doi:10.1007/s11906-019-0964-5 · Cited by 118 · see citing works
Improving obesity and blood pressure
Tanaka, M. (2019) · Hypertension Research · doi:10.1038/s41440-019-0348-x · Cited by 110 · see citing works
Bellinger, D. L., & Lorton, D. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19041188 · Cited by 104 · see citing works
Gender Differences and Cardiometabolic Risk: The Importance of the Risk Factors
Meloni, A., Dessalvi, C. C., Cugusi, L., Donataccio, M. P., Deidda, M., Sciomer, S., Gallina, S., Vassalle, C., Moscucci, F., Mercuro, G. G., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24021588 · Cited by 95 · see citing works
“The overactivity of the sympathetic nervous system is not only a hallmark of obesity, but it may also take part in the development of metabolic disturbance and cardiovascular complications in obese subjects [62,63].”
BackgroundNovel Invasive and Noninvasive Cardiac-Specific Biomarkers in Obesity and Cardiovascular Diseases
Parsanathan, R., & Jain, S. K. (2019) · Metabolic Syndrome and Related Disorders · doi:10.1089/met.2019.0073 · Cited by 95 · see citing works
Ryu, Y., Kim, S. W., Kim, Y. Y., & Ku, S. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20112720 · Cited by 90 · see citing works
“However, given that excess sympathetic activity is considered a reason for obesity as well as insulin resistance [63], a clear relationship among the manifestation of PCOS-like symptoms in this model seems to be elusive.”
BackgroundMyocardial Energetics in Obesity
Rayner, J. J., Peterzan, M. A., Watson, W. D., Clarke, W. T., Neubauer, S., Rodgers, C. T., & Rider, O. J. (2020) · Circulation · doi:10.1161/circulationaha.119.042770 · Cited by 91 · see citing works
Badimón, L., Bugiardini, R., Cenko, E., Cubedo, J., Dorobanţu, M., Duncker, D. J., Estruch, R., Miličić, D., Tousoulis, D., Vasiljević, Z., et al. (2017) · European Heart Journal · doi:10.1093/eurheartj/ehx181 · Cited by 88 · see citing works
“els and whole-body noradrenaline plasma spillover compared with lean subjects.(35) See Supplementary material online, Appendix.”
MethodThe Interlinked Rising Epidemic of Insufficient Sleep and Diabetes Mellitus
Chattu, V. K., Chattu, S. K., Burman, D., Spence, D. W., & Pandi-Perumal, S. R. (2019) · Healthcare · doi:10.3390/healthcare7010037 · Cited by 87 · see citing works
“Sleep disorders lead to insulin resistance and beta-cell dysfunction through various pathways [61].”
BackgroundLinoleic acid and the regulation of glucose homeostasis: A review of the evidence
Hamilton, J., & Klett, E. L. (2021) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2021.102366 · Cited by 87 · see citing works
Reciprocal activity of AgRP and POMC neurons governs coordinated control of feeding and metabolism
Solís, A. J. D., Río-Martín, A. D., Radermacher, J., Chen, W., Steuernagel, L., Bauder, C. A., Eggersmann, F. R., Morgan, D. A., Lena, C. A., Sue, M. W., et al. (2024) · Nature Metabolism · doi:10.1038/s42255-024-00987-z · Cited by 91 · see citing works
“These neurocircuits integrate diverse internal and external signals, and, besides regulating food intake, they regulate numerous metabolic responses in peripheral organs 4 .”
Yang, T., Ahmari, N., Schmidt, J. T., Redler, T., Arocha, R., Pacholec, K., Magee, K. L., Malphurs, W. L., Owen, J. L., Krane, G. A., et al. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00220 · Cited by 82 · see citing works
Mechanistic investigations of diabetic ocular surface diseases
Zhou, Q., Yang, L., Wang, Q., Li, Y., Wei, C., & Xie, L. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1079541 · Cited by 81 · see citing works
Neeland, I. J., Das, S. R., Simon, D. N., Diercks, D. B., Alexander, K. P., Wang, T. Y., & de Lemos, J. A. (2017) · European Heart Journal - Quality of Care and Clinical Outcomes · doi:10.1093/ehjqcco/qcx010 · Cited by 79 · see citing works
“Alterations in the autonomic nervous system may also result from extreme obesity and potentiate its metabolic effects.(24) Finally, although referral rates for cardiac rehabilitation were not different across BMI groups in our study, individuals with extreme obesity are more likely to have orthopedic/ musculoskeletal…”
BackgroundFerdinand, K. C., Balavoine, F., Besse, B., Black, H. R., Desbrandes, S., Dittrich, H. C., Nesbitt, S. D., & On behalf of the NEW HOPE Investigators (2019) · Circulation · doi:10.1161/circulationaha.119.040070 · Cited by 79 · see citing works
Physiological and therapeutic effects of carnosine on cardiometabolic risk and disease
Baye, E., Ukropcová, B., Ukropec, J., Hipkiss, A. R., Aldini, G., & de Courten, B. V. (2016) · Amino Acids · doi:10.1007/s00726-016-2208-1 · Cited by 77 · see citing works
Risk factors for premature ventricular contractions in young and healthy adults
von Rotz, M., Aeschbacher, S., Bossard, M., Schoen, T., Blum, S., Schneider, S., Estis, J., Todd, J. A., Risch, M., Risch, L., et al. (2016) · Heart · doi:10.1136/heartjnl-2016-309632 · Cited by 76 · see citing works
Wulsin, L. R., Herman, J. P., & Thayer, J. F. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.12.010 · Cited by 73 · see citing works
“, 2008)? Evidence suggests that dysregulation of the sympathetic and parasympathetic systems during major depressive episodes plays a role in the relationship between clinical depression and the increased risk for insulin resistance, followed by the development and progression of type II diabetes (Thorp and Schlaich,…”
BackgroundInfluentialCaturano, A., Galiero, R., Pafundi, P. C., Cesaro, A., Vetrano, E., Palmiero, G., Rinaldi, L., Salvatore, T., Marfella, R., Sardu, C., et al. (2021) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2021.108959 · Cited by 73 · see citing works
Does the sympathetic nervous system contribute to the pathophysiology of metabolic syndrome?
Moreira, M. C. D. S., Pinto, I. S. D. J., Mourão, A. A., Fajemiroye, J. O., Colombari, E., Reis, Â. A. D. S., Freiria-Oliveira, A. H., Neto, M. L. F., & Pedrino, G. R. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2015.00234 · Cited by 72 · see citing works
“Furthermore, the activation of sympathetic nerves in target organs like liver, pancreas, skeletal muscle, and adipose tissue can elicit acute catabolic responses (i.e., glycogenolysis and lipolysis) (Thorp and Schlaich, 2015).”
BackgroundCentral Nervous System Control of Glucose Homeostasis: A Therapeutic Target for Type 2 Diabetes?
Mirzadeh, Z., Faber, C. L., & Schwartz, M. W. (2022) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-052220-010446 · Cited by 68 · see citing works
Maniaci, A., Lavalle, S., Parisi, F. M., Barbanti, M., Cocuzza, S. G., Iannella, G., Magliulo, G., Pace, A., Lentini, M., Masiello, E., et al. (2024) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd11070204 · Cited by 68 · see citing works
“This includes investigating the potential of neuromodulation techniques, such as renal denervation or baroreceptor stimulation, as adjunctive therapies for managing sympathetic hyperactivity in OSA [127].”
BackgroundBioelectronic medicine for the autonomic nervous system: clinical applications and perspectives
Cracchiolo, M., Ottaviani, M. M., Panarese, A., Strauss, I., Vallone, F., Mazzoni, A., & Micera, S. (2021) · Journal of Neural Engineering · doi:10.1088/1741-2552/abe6b9 · Cited by 65 · see citing works
“Metabolic diseases are also related to the overactivation of the sympathetic nervous system, which leads to hypertension and insulin resistance, preliminary conditions for developing type 2 diabetes [197].”
BackgroundAltered Gut Microbiota: A Link Between Diet and the Metabolic Syndrome
Velasquez, M. T. (2018) · Metabolic Syndrome and Related Disorders · doi:10.1089/met.2017.0163 · Cited by 63 · see citing works
“54,55 Excessive caloric intake stimulates the activity of SNS through b - adrenergic receptor action on target tissues, which then activates thermogenesis, as a means of the body’s defense against diet-induced obesity.”
Rafeh, R. W., Viveiros, A., Oudit, G. Y., & EL‐Yazbi, A. F. (2020) · Clinical Science · doi:10.1042/cs20190227 · Cited by 63 · see citing works
Carnagarin, R., Tan, K., Adams, L. A., Matthews, V. B., Kiuchi, M. G., Lugo‐Gavidia, L. M., Lambert, G. W., Lambert, É., Herat, L. Y., & Schlaich, M. P. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22084241 · Cited by 59 · see citing works
“Heightened sympathetic activation has been demonstrated using gold standard techniques such as microneurography and nor-adrenaline spillover from whole body and from individual organs in patients with liver cirrhosis [46] and metabolic diseases [13,47].”
MethodSelf-citationRen, W., Chen, J., Wang, W., Li, Q., Yin, X., Zhuang, G., Zhou, H., & Zeng, W. (2024) · Neuron · doi:10.1016/j.neuron.2023.12.012 · Cited by 59 · see citing works
Sun, J., Xi, B., Yang, L., Zhao, M., Juonala, M., & Magnussen, C. G. (2020) · Obesity Reviews · doi:10.1111/obr.13138 · Cited by 56 · see citing works
Insulin resistance: a new consequence of altered carotid body chemoreflex?
Conde, S. V., Ribeiro, M. J., Melo, B. F., Guarino, M. P., & Sacramento, J. F. (2016) · The Journal of Physiology · doi:10.1113/jp271684 · Cited by 54 · see citing works
“1) (Lambert GW et al. 2010; Lambert EA et al. 2015; Thorp & Schlaich, 2015).”
BackgroundGutgesell, R. M., Khalil, A., Liśkiewicz, A., Maity‐Kumar, G., Novikoff, A., Grandl, G., Liśkiewicz, D., Coupland, C., Karaoglu, E., Akindehin, S., et al. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01294-x · Cited by 56 · see citing works
“…the periphery and the brain, the PNS is well positioned to control energy metabolism, not only by modulating glycaemia via regulation of sympathetic outflow to the skeletal muscle 32 , but also by promoting GIP-induced vasodilation in the mesenteric vasculature, including the adipose tissue 33,34 .”
Margonato, D., Galati, G., Mazzetti, S., Cannistraci, R., Perseghin, G., Margonato, A., & Mortara, A. (2020) · Heart Failure Reviews · doi:10.1007/s10741-020-10024-2 · Cited by 54 · see citing works
“Elevated sympathetic activity is widely known as a major risk factor for renal disease [27, 28] and a known feature of diabetic patients [29].”
BackgroundFerroptosis increases obesity: Crosstalk between adipocytes and the neuroimmune system
Zhang, S., Sun, Z., Jiang, X. Y., Lu, Z., Ding, L., Li, C., Tian, X., & Wang, Q. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1049936 · Cited by 52 · see citing works
Carotid body: a metabolic sensor implicated in insulin resistance
Conde, S. V., Sacramento, J. F., & Guarino, M. P. (2018) · Physiological Genomics · doi:10.1152/physiolgenomics.00121.2017 · Cited by 52 · see citing works
Peikert, A., Fontana, M., Solomon, S. D., & Thum, T. (2025) · European Heart Journal · doi:10.1093/eurheartj/ehaf524 · Cited by 56 · see citing works
Hyperglycemia induces defective Ca2+ homeostasis in cardiomyocytes
Sorrentino, A., Borghetti, G., Zhou, Y., Cannata, A. N., Meo, M., Signore, S., Anversa, P., Leri, A., Goichberg, P., Qanud, K., et al. (2016) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00737.2016 · Cited by 49 · see citing works
Alarcón, G., Roco, J., Medina, M., Medina, A., Peral, M. D. L. Á., & Jerez, S. J. (2018) · International Journal of Obesity · doi:10.1038/s41366-018-0020-6 · Cited by 48 · see citing works
“Central sympathetic over-activity plays a pivotal role in the etiology and complications of MS [38].”
BackgroundFornes, R., Simin, J., Nguyen, M. H., Cruz, G., Crisosto, N., van der Schaaf, M., Engstrand, L., & Brusselaers, N. (2022) · Reproductive Biology and Endocrinology · doi:10.1186/s12958-022-00905-6 · Cited by 44 · see citing works
Vasomotor symptoms and metabolic syndrome
Tuomikoski, P., & Savolainen-Peltonen, H. M. (2017) · Maturitas · doi:10.1016/j.maturitas.2016.12.010 · Cited by 48 · see citing works
Lemche, E., Чабан, О., & Lemche, A. V. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00142 · Cited by 49 · see citing works
“…strongly amongst different ethnicities, and because the overall gene pool did not substantially change over the last decades, the obesity and diabetes epidemic was assumed resulting mainly from detrimental environment factors, such as food availabilities, diet habits, or sedentary lifestyles.”
BackgroundInfluentialWang, H., Gu, Y., Zheng, L., Liu, L., Meng, G., Wu, H., Xia, Y., Bao, X., Shi, H., Sun, S., et al. (2018) · Liver International · doi:10.1111/liv.13896 · Cited by 47 · see citing works
The Role of SGLT2 Inhibitor on the Treatment of Diabetic Retinopathy
Sha, W., Wen, S., Chen, L., Xu, B., Lei, T., & Zhou, L. (2020) · Journal of Diabetes Research · doi:10.1155/2020/8867875 · Cited by 47 · see citing works
“We showed for the first time that norepinephrine, the main neurotransmitter of SNS, upregulates the expression of SGLT2 protein in human proximal renal tubular cells [54].”
BackgroundMiyamoto, Y., Honda, A., Yokose, S., Nagata, M., & Miyamoto, J. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12062253 · Cited by 48 · see citing works
“In humans, chronic activation of the SNS has been reported in patients with obesity, metabolic syndrome, and type 2 diabetes [48,49].”
BackgroundWang, X., Ren, J., Ren, H., Song, W., Qiao, Y., Zhao, Y., Linghu, L., Cui, Y. Y., Zhao, Z., Chen, L., et al. (2023) · Scientific Reports · doi:10.1038/s41598-023-40036-5 · Cited by 48 · see citing works
Carotid body chemosensitivity: early biomarker of dysmetabolism in humans
Cunha-Guimaraes, J. P., Guarino, M. P., Timóteo, A. T., Caires, I., Sacramento, J. F., Ribeiro, M. J., Selas, M., Santiago, J. C. P., Carmo, M. M., & Conde, S. V. (2020) · European Journal of Endocrinology · doi:10.1530/eje-19-0976 · Cited by 45 · see citing works
The role of metabolic syndrome in sudden cardiac death risk: Recent evidence and future directions
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Thiesse, L., Rudzik, F., Spiegel, K., Leproult, R., Pieren, R., Wunderli, J. M., Foraster, M., Héritier, H., Eze, I. C., Meyer, M., et al. (2018) · Environment International · doi:10.1016/j.envint.2018.05.036 · Cited by 43 · see citing works
“, 1996), or increased sympathetic nervous activity and catecholamine levels (Lembo et al., 1994; Thorp and Schlaich, 2015), are Fig.”
BackgroundTheodorakis, N., Kreouzi, M., Pappas, A., & Nikolaou, M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252413438 · Cited by 43 · see citing works
Mendoza, M. F., Kachur, S. M., & Lavie, C. J. (2020) · Current Opinion in Cardiology · doi:10.1097/hco.0000000000000749 · Cited by 42 · see citing works
Lona, G., Hauser, C., Köchli, S., Infanger, D., Endes, K., Schmidt‐Trucksäss, A., & Hanssen, H. (2021) · Pediatric Research · doi:10.1038/s41390-020-01278-5 · Cited by 43 · see citing works
Oroian, B. A., Ciobica, A. S., Timofte, D. V., Ștefănescu, C., & Șerban, I. L. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/5599265 · Cited by 45 · see citing works
“Metabolic disorders are equally correlated with a heightened SNS activity [122, 123], such as enhanced muscle sympathetic nerve activity.”
BackgroundSympathetic innervation of the mouse kidney and liver arising from prevertebral ganglia
Torres, H., Huesing, C., Burk, D. H., Molinas, A., Neuhuber, W., Berthoud, H., Münzberg, H., Derbenev, A. V., & Zsombok, A. (2021) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00079.2021 · Cited by 40 · see citing works
Coordinated human sleeping brainwaves map peripheral body glucose homeostasis
Vallat, R., Shah, V. D., & Walker, M. P. (2023) · Cell Reports Medicine · doi:10.1016/j.xcrm.2023.101100 · Cited by 39 · see citing works
“One possible mechanism explaining the recognized link between deficient sleep and impaired blood glucose control is an alteration of autonomic sympathovagal balance resulting in a biased state of sympathetic activity over parasympathetic activity,(30) which may chronically lead to insulin resistance and metabolic dysf…”
BackgroundSvensson, M. K. E., Lindmark, S., Wiklund, U., Rask, P., Karlsson, M., Myrin, J., Kullberg, J., Johansson, L. O. M., & Eriksson, J. W. (2016) · Cardiovascular Diabetology · doi:10.1186/s12933-016-0411-8 · Cited by 38 · see citing works
“Elevated activity of the SNS has thus been proposed as a causal factor in the “insulin resistance syndrome” [7].”
BackgroundRamos, J. S., Dalleck, L. C., Borrani, F., Beetham, K. S., Mielke, G. I., Dias, K. A., Wallen, M. P., Keating, S. E., Fassett, R. G., & Coombes, J. S. (2017) · International Journal of Cardiology · doi:10.1016/j.ijcard.2017.07.063 · Cited by 38 · see citing works
“Moreover, impaired CAF has also been put forth as an underlying cause of MetS [4].”
BackgroundKraft, G., Vrba, A., Scott, M. F., Allen, E. J., Edgerton, D. S., Williams, P. E., Vafai, S. B., Azamian, B. R., & Cherrington, A. D. (2019) · Diabetes · doi:10.2337/db18-1209 · Cited by 38 · see citing works
“Elevated sympathetic nerve activity has been hypothesized to be the cornerstone linking obesity and the metabolic syndrome (17,18), but it is not clear whether sympathetic nerve overactivity is the consequence or the cause of metabolic abnormalities.”
BackgroundXiao, Y., Yin, S., Wang, J., Cui, J., Yang, Z., Wang, J., & Bai, Y. (2023) · Frontiers in Public Health · doi:10.3389/fpubh.2023.1137191 · Cited by 37 · see citing works
“Compared to people without it, overactivated sympathetic activity and decreased vagal activity are more likely to be seen in people with MetS and depression (18, 23).”
BackgroundResistin, an Adipokine with Non-Generalized Actions on Sympathetic Nerve Activity
Badoer, E., Kosari, S., & Stebbing, M. J. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2015.00321 · Cited by 36 · see citing works
Crosstalk between Schizophrenia and Metabolic Syndrome: The Role of Oxytocinergic Dysfunction
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“Preceding autonomic nervous system dysfunction in persons with metabolic syndrome [306] as well as in those with schizophrenia [307] is another neurobiological factor that is common to schizophrenia and metabolic syndrome.”
BackgroundA systematic review and meta-analysis of heart rate variability in COPD
Alqahtani, J. S., Aldhahir, A. M., Alghamdi, S. M., Ghamdi, S. S. A., AlDraiwiesh, I. A., Alsulayyim, A. S., Alqahtani, A., Alobaidi, N. Y., Saikhan, L. A., AlRabeeah, S. M., et al. (2023) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2023.1070327 · Cited by 36 · see citing works
“Interestingly, common chronic diseases such as cancer (44), obesity and metabolic syndrome (45), heart failure (46), cirrhosis (47), smoking (48), and hypertension (49), are associated with an activation of sympathetic and a decrease in parasympathetic nervous activity.”
BackgroundSohn, R. E., & Jenei‐Lanzl, Z. (2023) · NeuroImmunoModulation · doi:10.1159/000531798 · Cited by 37 · see citing works
“All the above-mentioned OA comorbidities have one major characteristic in common: they all involve SNS over-activity resulting in chronic low-grade in-fl ammation [169, 176 – 182].”
BackgroundObesity and hypertension: Obesity medicine association (OMA) clinical practice statement (CPS) 2023
Clayton, T. L., Fitch, A., & Bays, H. E. (2023) · Obesity Pillars · doi:10.1016/j.obpill.2023.100083 · Cited by 36 · see citing works
“…distention, which, along with effects upon autonomic nervous and baroreflex systems, can cause relative or absolute reduction in blood pressure (postprandial hypotension), increased heart rate (commonly detected by wearable heart rate technology after meals), and sometimes lightheadedness [24,26].”
BackgroundInfluentialType 2 diabetes – unmet need, unresolved pathogenesis, mTORC1-centric paradigm
Bar‐Tana, J. (2020) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-020-09545-w · Cited by 34 · see citing works
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Wu, Q., Zhao, M. F., He, X., Xue, R., Li, D., Yu, X., Wang, S., & Zang, W. (2021) · Cell Cycle · doi:10.1080/15384101.2021.1965734 · Cited by 34 · see citing works
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“It is our view that the widespread use of this model should be questioned, given that: (1) The Zucker diabetic rat lacks functional leptin receptors (fa/fa genotype), because leptin receptor deficiency is infrequently seen in obese and T2D humans since leptin receptor mutations are relatively rare [28]; (2) we have sh…”
Sacramento, J. F., Martins, F. O., Rodrigues, T., Matafome, P. N., Ribeiro, M. J., Olea, E., & Conde, S. V. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00262 · Cited by 34 · see citing works
“There is accumulating evidences from animal and human studies showing that central sympathetic overactivity plays a pivotal role in the etiology and complications of insulin resistance (31, 32).”
BackgroundInfluences of lifestyle factors on cardiac autonomic nervous system activity over time
Hu, M. X., Lamers, F., de Geus, E. J. C., & Penninx, B. W. J. H. (2016) · Preventive Medicine · doi:10.1016/j.ypmed.2016.11.003 · Cited by 33 · see citing works
Cerebrovascular Disease: Consequences of Obesity-Induced Endothelial Dysfunction
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“The precise mechanism through which the brain regulates changes in hormone release with sleep deprivation is unknown, but one possibility is increased sympathetic nervous system activity [38].”
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Decoding Neural Metabolic Markers From the Carotid Sinus Nerve in a Type 2 Diabetes Model
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“Overactivation of the sympathetic nervous system (SNS) is an autonomic dysfunction associated with hypertension (HT) as well to insulin resistance (IR) and glucose intolerance, typical features of type 2 diabetes mellitus [1]–[4].”
BackgroundSacramento, J. F., Andrzejewski, K., Melo, B. F., Ribeiro, M. J., Obeso, A., & Conde, S. V. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21155545 · Cited by 33 · see citing works
“The sympathetic nervous system is known to play a role in the generation of metabolic diseases [3,4] and several factors have been postulated to be responsible for this increased sympathetic activation, such as hyperinsulinemia, hyperleptinemia,”
BackgroundExploring the Link between Oxidative Stress, Selenium Levels, and Obesity in Youth
Bizerea, T. O., Pitulice, L., Bizerea-Spiridon, O., & Moga, T. V. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25137276 · Cited by 32 · see citing works
“Activation of the sympathetic nervous system regulating the stress response, various mental health conditions, etc. [67–71].”
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Androgens and Blood Pressure Control
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- Authors
- Thorp, A. A., & Schlaich, M. P.
- Affiliations
- Baker Heart and Diabetes Institute (AU)
- Corresponding author
- Schlaich, Markus P.
- ORCID
- Schlaich, Markus P.
- Venue
- Journal of Diabetes Research
- Publisher
- Wiley
- Published
- 2015
- Volume
- 2015
- Pages
- 1-11
- ISSN
- 2314-6745 (ISSN-L)
- 2314-6753
- PMC
- PMC4430650
- OpenAlex
- W2066041574
- Cited by
- 425
- References
- 101
- Citations by year
- 2026: 28 · 2025: 42 · 2024: 36 · 2023: 44 · 2022: 40 · 2021: 45 · 2020: 48 · 2019: 40 · 2018: 33 · 2017: 31 · 2016: 32 · 2015: 5
- FWCI
- 4.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Diabetes Research (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- UWA Profiles and Research Repository (UWA) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Health and Medical Research Council
- Victorian Government’s Operational Infrastructure Support Program
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Keywords
- sympathetic nervous system, sympathetic hyperactivity, obesity, metabolic syndrome, energy homeostasis, abdominal obesity, insulin resistance, baroreflex sensitivity, hyperinsulinemia, adipokines, type 2 diabetes, cardiovascular disease, sympathetic activity, device therapy
- MeSH terms
- Animals, Humans, Obesity, Sympathetic Nervous System, Metabolic Syndrome
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